Elevated growth differentiation factor-15 in sepsis: clinical associations and immune cell context.

Background: Early clinical assessment in sepsis remains challenging because of marked heterogeneity in host responses and the limited biological resolution of existing severity scores and conventional inflammatory biomarkers in capturing integrated cellular stress responses. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that is elevated in critical illness; however, its clinical associations and immune cell-specific context in sepsis remain incompletely characterized. Methods: In this prospective observational exploratory study, serum GDF-15 concentrations were measured by enzyme-linked immunosorbent assay in a small cohort of adult patients with sepsis (n = 19) and healthy controls (n = 23). Associations between circulating GDF-15 levels, disease severity scores, markers of organ dysfunction, and inflammatory biomarkers were assessed using non-parametric correlation analyses. To provide biological context, publicly available single-cell RNA sequencing data (GSE217906) were analyzed to characterize immune cell-specific patterns of GDF15 expression during acute sepsis. Results: Circulating GDF-15 concentrations were markedly elevated in patients with sepsis compared with healthy controls (median 1390 vs. 1050 pg/mL). Among patients with sepsis, higher GDF-15 levels were consistently observed in those with greater disease severity, and increased levels of inflammatory biomarkers. Analysis of independent single-cell transcriptomic data demonstrated increased GDF15 expression in immune cells during acute sepsis, with relative enrichment observed primarily in plasma cells and monocytes. Exploratory receiver operating characteristic analyses suggested that circulating GDF-15 exhibited descriptive discrimination patterns for 28-day mortality that were directionally similar to those of established severity scores and conventional inflammatory biomarkers. Conclusion: Circulating GDF-15 levels are elevated in sepsis and are associated with disease severity, organ dysfunction, and inflammatory activity. Immune cell-specific enrichment of GDF15 expression provides biological context for its elevation during acute sepsis. Together, these findings suggest that GDF-15 may reflect, at least in part, systemic biological stress in critical illness, warranting further investigation in larger, well-characterized cohorts.